tbuckley/cabot-search huggingface dataset:
Immune checkpoint inhibitors in cutaneous squamous cell carcinoma: A systematic review of clinical trials.
Authors: Muhammad Yasir Anwar, Wajeeha Aiman, Muhammad Ashar Ali, Gurneel Dhanesar, Maha Zafar, Zainab Omar, Fatima Afzal, Gunwant K. Guron, Hamid Salim Shaaban, Michael Maroules
Journal: Journal of Clinical Oncology (2023)

e21529 Background: Cutaneous squamous cell carcinoma (cSCC) with high-risk features is primarily treated with radiations or surgically. However, locally advanced (LA) or metastatic cSCC (mcSCC) may not be managed surgically and require systemic therapy. In this systematic review, we will assess the efficacy of immune checkpoint inhibitors (ICIs) in patients with resectable, LA, or mcSCC. Methods: A literature search was performed on PubMed, Embase, and clinicaltrials.gov with keywords, “cutaneous squamous cell carcinoma” and “immune checkpoint inhibitor” from the inception of data till 12/31/22. After screening of 883 articles, 8 clinical trials (N = 513) were included. Results: In 8 clinical trials (N = 513), 205 patients had LA cSCC, 99 patients had resectable cSCC, and 209 patients had mcSCC. 81 patients were newly diagnosed while 432 patients were relapsed/refractory (RR). Cemiplimab was used to treat 262 patients, pembrolizumab for 227 patients, and nivolumab for 24 patients. In 2 clinical trials (N = 142) on RR LA cSCC, complete response (CR), partial response (PR), overall response (OR), and progressive disease (PD) were 13-17%, 31-33%, 44-50%, and 12-17%, respectively, in patients treated with ICIs. In 3 clinical trials (N = 175) on RR mcSCC, CR, PR, OR, and PD were 7-18%, 25-41%, 36-64%, and 16-26%, respectively. In two clinical trials (N = 81) on ND cSCC patients, CR, PR, OR, and PD were 0-7%, 35-58%, 42-58%, and 32-20%, respectively. In 2 clinical trials (N = 99) on resectable cSCC, pathological CR, pathological major response, and PD were 51-75%, 13-20%, and 10%, respectively, in patients treated with ICIs. Table. Conclusions: ICIs including cemiplimab, pembrolizumab, and nivolumab were effective in the treatment of resectable, LA, and mcSCC. ICIs were effective in the treatment of both R/R and treatment naïve mcSCC. However, no results were available for randomized clinical trials and large-scale randomized studies are needed to confirm these results. [Table: see text]
DURTRERAD: A phase II open-label study evaluating feasibility and efficacy of durvalumab (D) and durvalumab plus tremelimumab (DT) in combination with radiotherapy (RT) in non-resectable locally advanced HPV-negative head and neck squamous cell carcinoma (LA-HNSCC).
Authors: Ulrich Keilholz, Thomas Christoph Gauler, Carmen Stromberger, Grzegorz Kofla, Maike de Wit, Ramona Mette, Susen Burock, Konrad Friedrich Klinghammer
Journal: Journal of Clinical Oncology (2023)

2611 Background: Concurrent platinum-based chemo-RT is the standard treatment for LA-HNSCC, despite of limited efficacy in poor-risk patients and long-term toxicity. Targeting PD-L1 with D has activity in recurrent/metastatic (RM)-HNSCC, and the combination with the CTLA4 targeting agent T was considered to augment the immunotherapy efficacy of a chemotherapy-free regimen. Thus DURTRERAD was designed as a randomized two-arm phase II study to investigate, whether D or DT combined with RT was feasible in the patient population and a 1-year progression free survival rate of 50% was reached. Methods: The phase II study planned to enroll 60 patients in each treatment arm. Key selection criteria were patients with advanced HPV negative unresectable HNSCC planned for definitive radiotherapy. Treatments: First dose of immunotherapy 14 days prior to start of RT (70Gy over 7 weeks). D (1500mg q 3 weeks x 13) or DT (D: 1500mg q 3 weeks x 13 + T: 4 x 75 mg in weeks 5,9,13,17). Planned treatment duration was 51 weeks in both arms. Treatment was considered feasible in case of &lt;10% treatment discontinuations. An interim analysis for feasibility was planned after treatment of 6 patients per arm and a futility analysis was performed after treatment of 18 patients, resulting in premature closure of the trial. Results: Patient accrual in 4 centers in Germany from 9/2018 - 9/2020. The interim feasibility analysis of DT revealed that 5/6 patients stopped treatment due to 1 grade 5 and 1 grade 4 immune related AE and 3 non-immune related AEs, respectively. Thus, the DT arm was prematurely terminated, and only the D monotherapy arm continued. Futility analysis of D monotherapy: One of 12 patients stopped treatment due to immune related toxicity, and 7 patients experienced disease progression on treatment or died within the first year. The median PFS was 39 weeks, the 1 year PFS rate was 42%. Conclusions: Even though D was previously proven as an active agent in RM-HNSCC, and there DT was not associated with increased toxicity, DT in combination with RT was not feasible in our poor prognostic, vulnerable patient cohort of HPV negative LA-HNSCC. D monotherapy in combination with RT was well tolerated, but revealed a low level of efficacy, when administered in the trial schedule, starting 2 weeks prior to RT. Similar to results in lung cancer, start of immunotherapy after completion of radiotherapy may be of interest. Clinical trial information: NCT03624231 .
Circulating chromatin conformation signatures to enhance PSA positive predictive value and overall accuracy for prostate cancer detection.
Authors: Alexandre Akoulitchev, Ewan Hunter, Matthew Salter, Ryan Powell, Tarun Naithani, Jayne Green, Francesca Fiorentino, Hashim Uddin Ahmed, Dmitri Pchejetski, Mathias Winkler
Journal: Journal of Clinical Oncology (2023)

e17016 Background: Prostate cancer (PCa) has a high lifetime prevalence (one out of six men), but currently there is no widely accepted screening programme. Widely used prostate specific antigen (PSA) test at cut-off of 3.0 ng/mL does not have sufficient accuracy for detection of any prostate cancer, resulting in numerous unnecessary prostate biopsies in men with benign disease and false reassurance in some men with PCa. We have recently identified circulating chromosome conformation signatures (CCSs, Episwitch PCa test) allowing PCa detection and risk stratification in line with standards of clinical PCa staging. The purpose of this study was to determine whether combining the Episwitch PCa test with the PSA test will increase its diagnostic accuracy. Methods: n = 109 whole blood samples of men enrolled in the PROSTAGRAM screening pilot study and n = 38 samples of patients with established PCa diagnosis and cancer-negative controls from Imperial College NHS Trust were used. Samples were tested for PSA, and the presence of CCSs in the loci encoding for of DAPK1, HSD3B2, SRD5A3, MMP1, and miRNA98 associated with high-risk PCa identified in our previous work. Results: PSA &gt; 3 ng/mL alone showed a low positive predicted value (PPV) of 0.14 and a high negative predicted value (NPV) of 0.93. EpiSwitch alone showed a PPV of 0.91 and a NPV of 0.32. Combining PSA and Episwitch tests has significantly increased the PPV to 0.81 although reducing the NPV to 0.78. Furthermore, integrating PSA, as a continuous variable (rather than a dichotomised 3 ng/mL cut-off), with EpiSwitch in a new multivariant stratification model, Prostate Screening EpiSwitch (PSE) test, has yielded a remarkable combined PPV of 0.93 and NPV of 0.95 when tested on the independent prospective cohort. Conclusions: Our results demonstrate that combining the standard PSA readout with circulating chromosome conformations (PSE test) allows for significantly enhanced PSA PPV and overall accuracy for PCa detection. The PSE test is accurate, rapid, minimally invasive, and inexpensive, suggesting significant screening diagnostic potential to minimise unnecessary referrals for expensive and invasive MRI and/or biopsy testing, with further extended prospective blinded validation of the new combined signature in a screening cohort with low cancer prevalence as the next step for PSE adoption in PCa screening.
Phase 1B study of avelumab and whole brain radiotherapy (WBRT) in patients with leptomeningeal disease (LMD) from epithelial carcinomas: Final results and molecular analyses with single cell RNA sequencing.
Authors: Yolanda Pina, Ann Chen, John Arrington, Robert J Macaulay, Nam D. Tran, James K Liu, Sepideh Mokhtari, Jiannong Li, Vincent Law, Solmaz Sahebjam, Kamran A. Ahmed, Ben C. Creelan, Jhanelle Elaine Gray, Brittany Evernden, Nikhil I. Khushalani, Inna Smalley, Michael A. Vogelbaum, Michael Yu, Keiran Smalley, Peter A. J. Forsyth
Journal: Journal of Clinical Oncology (2023)

2598 Background: Leptomeningeal disease (LMD) from epithelial cancer has a dismal prognosis with median overall survival (OS) of 3-4 months (mo) using PD-1 axis blocking therapy. Preclinical studies showed that this combination promotes antigen presentation within the CSF compartment, increases BBB permeability and increases ingress of activated T cells into the meninges/CSF space. In an open-label phase IB trial, we tested the safety and efficacy of Avelumab in combination with WBRT in patients with LMD (NCT0371768). Methods: Patients received concurrent Avelumab 800 mg IV q2 weeks for up to 5 cycles (until PD or unacceptable toxicity) with WBRT 3000 cGy in 10 daily fractions. Primary endpoints were safety/DLTs and 3-month OS. Secondary endpoints included CSF T-cell transcriptome trajectory i.e., single cell RNA sequencing (scRNAseq). Patients with prior PD-1/PD-L1/CTLA-4/CD137 targeting therapy within 6 mo were excluded. Results: 15 patients were enrolled with disease sites that included breast (8), lung (4), nasopharyngeal (1), ovary (1), and pancreas (1). Patients were 87% female, median age 59 range 32-82. One patient did not complete WBRT. Two of 15 patients had grade 3/4 immune-related AEs (i.e., hypoadrenalism, hypothyroidism, lymphopenia); 5 patients had treatment-related &lt;grade 3 AEs, including hypoadrenalism, anemia, diarrhea, hypothyroidism, lymphopenia, thrombocytopenia, leukopenia). There were no grade 5 toxicities. Median follow up was 3.7 mo (range, 0.9-36.8 mo; 95% CI 1.3-14.7 mo). The median follow-up time for survival analyses of the study was 19.8 mo. Ten out of 15 patients (66.7%) were alive at 3 mo. Median OS was 10.5 (95% CI 1.2 - 19.8 mo). 1-year OS was 44% (95% CI: 19-68%). Median PFS was 4.3 mo (95% CI, 0.9-15.2 mo), Fig. 3B. Two patients remain alive and clinically well. ScRNAseq analyses are underway; signatures correlated with outcomes in short versus long term survivors. Conclusions: The combination of Avelumab and WBRT is safe, well tolerated, and demonstrates encouraging activity in patients with LMD with an OS that is longer than other published series. Multiple platform interrogation of CSF will be used to explore mechanisms of LMD response and resistance. Functional studies of scRNAseq and short versus long term survivors should be further explored. Clinical trial information: NCT03719768 .
Thoracic SMARCA4-deficient undifferentiated tumor: A clinicopathologic study.
Authors: Janna Shold, Ameer Hamza
Journal: Journal of Clinical Oncology (2023)

e14642 Background: Thoracic SMARCA4-deficient undifferentiated tumor is a high-grade malignant neoplasm that frequently shows undifferentiated morphology and deficiency of SMARCA4. There is limited data in literature for this entity. The purpose of this report is to describe clinicopathologic features of this rare tumor in a series of 5 patients, diagnosed and treated at our institution. Methods: After approval from institutional review board, pathology department archive was searched for the patients with diagnosis of Thoracic SMARCA4-deficient undifferentiated tumor from January 2020 to December 2022. Data such as patient demographics, pathologic features including immunohistochemical stains, treatment and clinical outcome were collected. Results: Among 5 patients, 3 were male and 2 were female. Median age was 62 years (range 49 to 77 years). In three patients the primary site of the tumor was lung. One patient had tumor of the gastroesophageal junction while one patient had epicenter of the tumor in the paraspinous muscle. Diagnosis was made on biopsy specimen in all cases. All tumor showed undifferentiated histologic appearance. Rare cells with keratin positivity were observed in 2 specimens while 3 were completely negative for keratin stains. Focal TTF1 positivity was observed in one specimen while 4 were negative. Among neuroendocrine markers performed on variable number of cases, synaptophysin was positive in 4/4 cases while chromogranin was negative in 2/2 cases and INSM1 was negative in 1/1 case. PD-L1 (Dako 22C3) was performed on two specimens and showed less than 1% tumor cells to be positive. Next generation sequencing was performed on one specimen and showed pathogenic variants in TP53, CDKN2A, and APC genes and likely pathogenic variants in ATR, SMARCA4, and BCOR genes. Two patients received carbotaxol and radiation, one patient received FOLFOX, nivolumab and radiation, 1 patient pursued hospice care and 1 patient lost follow up. Two patients died 2 and 7 months after diagnosis. One patient is alive with metastatic disease 4 months after initial diagnosis. Conclusions: SMARCA4-deficient undifferentiated tumor is an aggressive malignancy that shows undifferentiated histology with synaptophysin positivity. From a diagnosis standpoint, Pathologists need to keep this entity in mind while working up tumors showing poorly differentiated to undifferentiated histology that are negative for most immunohistochemical markers. From clinical standpoint there is need to develop targeted therapy for this aggressive tumor.
ADJUBIL: A phase II study of immunotherapy with durvalumab and tremelimumab in combination with capecitabine or without capecitabine in adjuvant situation for biliary tract cancer.
Authors: Thorsten Oliver Goetze, Lisa Kochen, Doerthe Vortmeyer, Salah-Eddin Al-Batran, Timorshah Habibzada, Marius Brunner, Thomas Jens Ettrich, Maria A Gonzalez-Carmona, Claus-Henning Kohne, Dominik Paul Modest
Journal: Journal of Clinical Oncology (2023)

TPS4187 Background: Despite improvements in multidisciplinary management, patients with biliary tract cancer (BTC) have a poor outcome. Only 20% of patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. Data regarding pure adjuvant chemotherapy in BTC’s are conflicting and the SOC of the western world is currently capecitabine according to the British BILCAP- trial, even though BILCAP was formally negative. Based on the positive data for durvalumab in the TOPAZ- 1 – trial in BTC and for STRIDE- regimen in HCC according to the Himalaya- data, evaluation of IO- combination in the adjuvant setting seems to be promising. Preclinical studies indicate that the antibody combination results in stronger and more durable anti-tumor effects than single therapies by synergistically modulating the immunosuppressive tumor microenvironment which is particularly rich in cholangiocarcinoma. The aim of this study is the assessment of the clinical activity of the anti-PD-L1 (programmed- death 1-ligand) antibody durvalumab and the anti-CTLA-4 (cytotoxic T- lymphocyte-associated antigen 4) antibody tremelimumab in combination with or without capecitabine in patients with respectable BTC in the adjuvant situation. This is a randomized phase II study as a proof-of-concept for a potentially larger research program. Methods: The ADJUBIL trial is an open-label, multicenter phase II study, including patients with BTC after curative surgery with no previous systemic treatment. Patients are randomly assigned to receive tremelimumab (300mg, one dose) plus durvalumab (1500mg every 4 weeks; STRIDE, for a maximum of 12 months), with or without capecitabine (for 8 cycles). Forty evaluable patients will be enrolled in the study (1:1) to receive anticancer treatment until disease recurrence or intolerable toxicities. Primary objective is to assess the anti-tumor activity of the treatment in both arms by the recurrence-free survival rate after 12 months (RFS@12). Secondary endpoints are recurrence-free survival, overall survival, toxicity, and quality of life. Exploratory endpoints: Explore predictive biomarkers for recurrence-free survival and overall survival. Study start of the ADJUBIL trial was in June 2021. By January 2023, 12 centers across Germany have been initiated and a total of 8 out of 40 planned patients (1:1) have been enrolled. The study is currently ongoing. Clinical trial information: EUCTR2021-002389-41 .
Learning what matters in allogeneic transplant: Insights into older patient preferences in an age-friendly multidisciplinary clinic.
Authors: Adam Braun, William Dale, Jeanine Moreno, Peter T. Curtin, Sanjeet Dadwal, Terence Hung, Nini Huynh, Monzr M. Al Malki, Ryotaro Nakamura, Stephen J. Forman, Andrew S. Artz
Journal: Journal of Clinical Oncology (2023)

e24029 Background: HCT is increasingly being considered for older adults (60+) with blood cancers, with emerging data suggesting HCT imparts a survival benefit for eligible patients (pts). HCT-related morbidity and mortality remains significant in older adults, with no consensus on how to best prospectively evaluate HCT versus other approaches. Shared decision making (SDM) may help reconcile such treatment options for older adults. Understanding pts preferences (PP) and values is a cornerstone of SDM, yet no data exist in how to elicit and apply PP for older adults facing this treatment choice. Methods: We analyzed documented PP among the first 40 older adults from an ongoing IRB-approved prospective protocol enrolling HCT candidates ≥60 years to participate in a multi-disciplinary optimization clinic, the Aging &amp; Blood Cancers (ABC) clinic. The ABC clinic is comprised of pre-HCT consultations with a geriatrician, HCT physician, physical therapist, dietician and social worker and an ID physician. We reviewed the primary treating team documentation relative to the ABC clinic documentation, notes reviewed from HLA typing orders or documented plan for HCT. Categorization of PP consisted of any of the following: (1) care goals after HCT (e.g. cure, disease control, functional recovery, spending time with family/friends, attending life events), (2) toxicity concerns, and (3) pt rationale for proceeding to HCT. We included PP when summarized in the advanced care planning (ACP) documents if signed by a team member or referenced in their note. Findings were extracted by one physician and then reviewed by a second physician to adjudicate assignment as a PP. P-values were derived from incidence rates and chi-squared testing. Results: Among 40 pts with a median age of 74 yrs (range 60-), 856 notes and 38 ACP documents were reviewed. We found PP in 26 notes (2.9%) in 19 pts (47.5%). Of pts with PP documented, the primary team accounted for 4, compared to 14 pts in the ABC clinic (p &lt; 0.02). Notably, the primary team documented a risk:benefit discussion about HCT in 31 patients (p &lt; 0.0001). Among total PP (n = 19) the most common included functional recovery (73.6%), spending time with family or specific people (73.6%) and minimizing toxicity (42.1%). Less common PP were disease control/cure (31.6%) or avoiding the need for future disease treatments (15.8%). Conclusions: To our knowledge, this is the first study to document older adult PPs before HCT, finding them to be rarely documented. The older adult specific HCT clinic enhanced preference documentation, yet still in less than half of pts. Future studies to develop tools to better elicit and incorporate pt preferences should be prioritized to facilitate shared decision making for HCT among older adults.
Anti-drug antibodies related to CTLA-4, PD-1, or PD-L1 inhibitors across tumour types: A systematic review.
Authors: David J. James Pinato, Peter R Galle, Catherine R Mitchell, Kerigo Ndirangu, Zahra Ramji, Gabrielle Redhead, Richard S. Finn
Journal: Journal of Clinical Oncology (2023)

e14600 Background: Treatment-emergent anti-drug antibodies (ADAs) are postulated to reduce the efficacy of immune checkpoint inhibitors. A systematic review (SR) was conducted to evaluate the incidence of treatment-emergent ADAs with programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors and their impact on treatment outcomes in patients with cancer. Methods: Electronic databases MEDLINE, EMBASE and Cochrane Library were searched in February 2022 for studies reporting incidence of ADAs and the impact of immunogenicity on treatment efficacy in oncology patients treated with PD-1, PD-L1, or CTLA-4 checkpoint inhibitors. Results: Of the 4,612 articles identified, 34 publications reporting on 68 trials were included. An additional 41 and 32 records were identified from clinicaltrials.gov and packaging inserts respectively. In total, 141 trials of 15 checkpoint inhibitors and 16 tumour types were included. There was considerable variability in the reporting of ADAs, and comparisons between trials were challenging due to intra-study heterogeneity. The incidence of ADAs ranged from 0 to 74%. Across trials, in analyses with the largest sample sizes, atezolizumab was associated with the highest incidence of ADAs (29.6%), then nivolumab (12.2%), followed by the remaining treatments (0-4.4%). The incidence of neutralising antibodies (nAbs) mirrored ADA distribution, being highest for atezolizumab (4.3–27.5%) vs other treatments. Only 17 trials reported on ADA impact on treatment outcomes. Of 11 trials examining efficacy, two reported a negative effect of ADAs, eight reported no measurable effect and another had insufficient patient numbers. The impact of ADAs on treatment safety, and pharmacokinetics was also inconclusive. Conclusions: Treatment-emerging ADAs are inconsistently reported across trials and documented in up to 30% of subjects treated with checkpoint inhibitors across indications. Emergence of nAbs follows but does not perfectly mirror ADA titers, raising questions around the functional meaning of different ADAs. Standardised reporting of ADAs and nAbs should be advocated to facilitate more conclusive immunologic and clinical insight as to the relationship with ADAs and response. [Table: see text]